Over the past decade, myostatin, a negative regulator of muscle growth, has emerged as a novel therapeutic target for a number of muscle degenerative diseases including Duchene muscular dystrophy (DMD). Inhibition of myostatin promotes muscle growth, and therefore offers an indirect way of compensating muscle degeneration in muscular dystrophies (MD) without directly addressing the specific genetic defects. In a number of mouse MD models, myostatin inhibition has demonstrated substantial efficacies by transgenic technology, delivery of inhibitory proteins/antibodies or AAV gene vectors. However, the therapeutic potential and safety of myostatin inhibition has not been evaluated in large animal MD models, such as the DMD golden retriever muscular dystrophy (GRMD) dogs. We hypothesize that gene delivery of a canine myostatin propeptide, a natural and specific inhibitor of myostatin, by AAV vectors would enhance muscle growth and reduce atrophy, ameliorate dystrophic pathologies and improve muscle functions in the GRMD dogs. In close collaboration with the DMD Canine Model Center at UNC Chapel Hill, we propose to use the GRMD model to study two specific aims: 1) to examine gene expression and therapeutic effects after regional gene delivery in the hindlimbs; 2) to evaluate body-wide gene expression, muscle growth and wholebody functional improvement after systemic gene delivery. The success of this project will validate myostatin propeptide in the large animal DMD model and provide an enabling technology for myostatin inhibitor gene therapy for future clinical applications. PUBLIC HEALTH RELEVANCE: This proposal attempts to validate a therapeutic strategy for Duchenne muscular dystrophy by blocking a muscle growth inhibitor, termed myostatin, in a large animal model. Its success will provide an enabling technology for future clinical applications in muscular dystrophies.